B. anthracis is considered to be among the most attractive agents for use in bioterrorism due to its clinical virulence. It has recently been deployed as a weapon in the U.S. with an attendant 45% mortality, despite the aggressive use of potent antimicrobials. Novel approaches to the therapy of anthrax are needed. B. anthracis exerts its pathogenic effects primarily through the action of lethal toxin, a combination of two proteins elaborated by the organism after infection: protective antigen and lethal factor. Because the synthesis of B. anthracis toxin is dependent on receptor binding and subsequent activation by a specific serine protease, the use of a receptor antagonist, von Willebrand factor concentrate, and the protease inhibitors antithrombin-III and inter-alpha-inhibitor, may prevent initial intoxication. Interleukin-11 may prove useful at subsequent steps to inhibit toxin action by attenuating the pro-inflammatory cytokine response. These potential therapies are all endogenous proteins and have the advantage of favorable clinical track records and safety profiles when used for other indications. Most are licensed for use in humans and therefore clinically available. The effects of these interventions on the action of B. anthracis toxin will be investigated initially in murine peritoneal macrophages, a system generally susceptible to the lethal effects of this toxin. Measurements of inflammatory cytokines and cell viability assays will be used to assess the impact of the therapeutic interventions on the activity of B. anthracis toxin. The importance of the temporal delivery of toxin inhibition strategies will be determined by varying the timing of therapy relative to intoxication. The in vivo effects of these therapies will be studied in mice with survival as an end-point. If successful, this research will lead to future, collaborative studies involving animal challenges to determine whether toxin inhibitors will provide additive or synergistic benefits when used in conjunction with existing antimicrobial approaches for the therapy of anthrax. Since antithrombin-lll, interleukin-11 and von Willebrand factor are already approved for human use for other indications, it should be possible to rapidly move into clinical trials with the optimal combinations of agents as determined in these pre-clinical studies. [unreadable] [unreadable]